Pain is an essential sensation in the protection of the body from damaging influences. However, because said pain frequently persists after it has played its essential role, it becomes desirable to treat the subject to reduce the sensation of pain. Drugs which are effective to reduce pain, i.e., analgesics, act by different mechanisms. There are:
(1) drugs which reduce pain by treating its source, e.g., glyceryl trinitrate in the treatment of angina;
(2) drugs of the nonnarcotic, nonsteroidal, antiinflammatory, antipyretic type, which may act in part peripherally to relieve pain by inhibition of prostaglandin synthetase, or by an antiinflammatory effect, e.g., aspirin or acetaminophen; and
(3) drugs which act mainly on the perception of pain by the brain, e.g., morphine and certain morphine derivatives.
Analgesics are also classified by their mode of use. Thus, in general, when the intensity of pain is mild to moderate, a simple (mild) analgesic is given. However, when the pain is moderate to severe, a strong analgesic is indicated.
The most important strong analgesic compounds include opium preparations, purified alkaloids (e.g., morphine), semi-synthetic morphine modifications (e.g., oxymorphone) and various synthetic morphine-like compounds (phenyl piperidine structures). In addition to morphine itself, the most widely used analgesics are oxycodone, oxymorphone, levorphanol, methadone and pethidine (meperidine). Morphine is the standard to which strong analgesics are compared.
Morphine, which acts on the central nervous system to repress pain perception, causes drowsiness, euphoria (and sometimes dysphoria) and depresses respiration. Morphine and the many drugs related thereto incur high degrees of dependence. This is, of course, no problem in short-term treatment of pain, but becomes a serious problem in treatment of chronic pain.
Because the narcotic-like analgesics also act to depress the respiratory system, overdosage of such compounds is extremely dangerous. It has been found, however, that several N-allyl derivatives, including the N-allyl derivatives of morphine (nalorphine), levorphanol (levallorphan) and oxymorphone (naloxone), effectively antagonize overdoses of the opiate analgesics. Two of these, nalorphine and levallorphan, have some analgesic effects by themselves, but naloxone is a pure antagonist having no intrinsic analgesic activity. Naloxone is a versatile material which is capable of reversing the action (including the analgesia) of larger doses of a narcotic and which also antagonizes the emetic effect of meperidine. Though such antagonists have been shown to be effective in antagonizing overdoses of narcotics, they have not been shown to be effective in administration with narcotics to reverse respiratory depression without also reversing the desirable analgesic effects of the opiate. Thus, it would be highly desirable to obtain a compound which combines significant narcotic analgesic activity as well as narcotic antagonistic activity in the same molecule.
Since Lasagna and Beecher (Lasagna, L. and Beecher, H. K., "The Analgesic Effectiveness of Nalorphine and Nalorphine-Morphine Combinations", in Man. J. Pharmacol. Exp. Ther., 112, pp. 356-363, 1954) reported that the narcotic antagonist nalorphine also has analgetic properties in man, a wide-ranging search for agonist/antagonist compounds possessing both analgetic and narcotic antagonist properties has led to the discovery of a number of clinically useful agents (e.g., pentazocine, cyclazocine, butorphanol, nalbuphine) which have a lower abuse potential than pure narcotic agonist compounds. Generally, but with some exceptions, substitution of C.sub.n homologues, wherein n.gtoreq.2, for the N-methyl group in morphine, codeine, and other narcotics produces compounds which possess an antagonist component with or without loss of analgetic potency; thus within a single chemical series there may be compounds possessing pure agonist, combined agonist/antagonist, and pure antagonist properties (Jaffe, J. H. and Martin, W. R., "Narcotic Analgesics and Antagonists", in The Pharmacological Basis of Therapeutics, L. S. Goodman and A. Gilman (Eds.), MacMillan Publishing Co., Inc., New York, 1975, p. 272).
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